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. 2012 Oct;18(10):834-40.
doi: 10.1111/j.1755-5949.2012.00379.x. Epub 2012 Aug 25.

Importance of riboflavin kinase in the pathogenesis of stroke

Ying-Xin Zou  1 , Xiu-Hua Zhang, Feng-Yun Su, Xia Liu
Affiliations

Affiliation

  • 1 Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.

Importance of riboflavin kinase in the pathogenesis of stroke

Ying-Xin Zou et al. CNS Neurosci Ther. 2012 Oct.
. 2012 Oct;18(10):834-40.
doi: 10.1111/j.1755-5949.2012.00379.x. Epub 2012 Aug 25.

Authors

Ying-Xin Zou  1 , Xiu-Hua Zhang, Feng-Yun Su, Xia Liu

Affiliation

  • 1 Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China.

Abstract

Aims: To explore risk factors for stroke independent of hypertension and the relationship between riboflavin kinase (RFK) and stroke.

Methods: Gene expression profiling in the brains of spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHRSP) was comparatively analyzed by gene chips. The differentially expressed gene RFK was further verified by q-PCR and Western blot. The protective role of RFK-regulated flavins (including riboflavin, flavin mononucleotide, and flavin adenine dinucleotide) in stroke was observed in middle cerebral artery occlusion (MCAO) mice. Influence of flavins on apoptosis and death in oxygen and glucose deprivation (OGD)-treated neurons was examined by flow cytometry. Bax and Bcl-2 proteins were detected by Western blot.

Results: Of the 76 differentially expressed genes, 41 genes were upregulated, and 35 genes were downregulated in SHRSP as compared with SHR. RFK was significantly downregulated in SHRSP. Flavins markedly decreased infarct area in MCAO mice, inhibited apoptosis and death in OGD-treated neurons, and decreased Bax protein expression.

Conclusions: Physiological downregulation of RFK may be a new potential risk factor for stroke, which probably affects the absorbance and utility of riboflavin and further destroys the protective effect of flavins on stroke. RFK might act as a therapeutic target for stroke.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

Figure 1

( A ) Real‐time PCR …

Figure 1

( A ) Real‐time PCR showed that riboflavin kinase ( RFK ) mRNA …

Figure 1
(A) Real‐time PCR showed that riboflavin kinase (RFK) mRNA level in the brain of stroke‐prone spontaneously hypertensive rats (SHRSP) was lower than that of spontaneously hypertensive rats (SHR) (n = 8, **P < 0.01). (B) Western blot showed that RFK protein level in the brain of SHRSP was lower than that of SHR (n = 3, **P < 0.01). Data are presented as mean±SD.
Figure 2

Figure 2

Flavin (riboflavin, FMN , or …

Figure 2

Flavin (riboflavin, FMN , or FAD ) treatment decreased the middle cerebral artery…

Figure 2
Flavin (riboflavin, FMN, or FAD) treatment decreased the middle cerebral artery occlusion (MCAO)‐induced infarct area in C57BL. The mice received flavins (3.5 mmol/kg; intraperitoneal injection), respectively, for 7 consecutive days before MCAO. At 24 h after MCAO, mice were anesthetized and the brains were immediately stained with triphenyltetrazolium chloride monohydrate (TTC) (n = 9, **P < 0.01).
Figure 3

Figure 3

Flavin (riboflavin, FMN , or …

Figure 3

Flavin (riboflavin, FMN , or FAD ) treatment inhibited the apoptosis rate and…

Figure 3
Flavin (riboflavin, FMN, or FAD) treatment inhibited the apoptosis rate and death rate of neurons induced by oxygen and glucose deprivation (OGD). Neurons were treated with different concentrations of flavin, respectively, in air and high glucose for 2 h and then in OGD for 1.5 h. After OGD, the apoptosis rate and death rate of neurons were immediately determined by flow cytometry. Data are presented as mean±SD (n = 3, *P < 0.05, **P < 0.01). (A) Images captured by flow cytometry. (B) Apoptosis rates. (C) Death rates.
Figure 4

Figure 4

Riboflavin or FMN treatment inhibited…

Figure 4

Riboflavin or FMN treatment inhibited the expression of Bax in neurons induced by…

Figure 4
Riboflavin or FMN treatment inhibited the expression of Bax in neurons induced by oxygen and glucose deprivation (OGD). Neurons were treated with flavin (riboflavin, FMN, and FAD), respectively, in air and high glucose for 2 h and then in OGD for 1.5 h. Protein was immediately extracted after OGD. Bax and Bcl‐2 were determined by Western blot. Data are presented as mean±SD (n = 3, *P < 0.05, **P < 0.01). (A) Images of the expression level of Bax and Bcl‐2 protein. (B) Relative expression of Bax in neurons treated with flavins. (C) Relative expression of Bcl‐2 in neurons treated with flavins.
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